Systemic Lupus Erythematosus (SLE)
Autoimmune diseases arise following an autoimmune response of the body against substances and tissues normally present in the body, resulting in continuous production of autoantibodies. Autoantibodies are able to activate the complement system and are deposited in many sites, thus inducing multi-organ inflammatory reactions and possibly damage to organs such as the kidneys. More than 5% of the world's population suffers from at least one of many autoimmune diseases, such as lupus, rheumatoid arthritis, scleroderma and others.
Systemic Lupus Erythematosus (SLE) is an autoimmune disease manifested as a chronic syndrome with a multi-factorial etiology and multiple symptoms affecting many organs such as the skin, the kidneys and the brain. The multifactorial complexity of SLE includes an overproduction of B cell activating factor (BAFF), an escape of auto-reactive B cells from apoptosis and a dis-balanced production of various inflammatory and protective cytokines Severe SLE involves glomerulonephritis, complications in the central nervous system, and recurrent thrombosis.
Several symptoms that are associated with SLE include: an increase in anti-cardiolipin auto-antibodies directed against cardiolipin present in the mitochondrial inner-membrane, an increase in anti-double-stranded DNA (anti-dsDNA) antibodies, a decrease in complement-system component concentration and Lupus Nephritis (LN)—an inflammation of the kidney leading to defects in renal function and possibly renal failure. Lupus Nephritis is often characterized by glomerulonephritis—an inflammation of the kidney glomeruli.
The disease course of SLE is unpredictable, comprising periods of illness (called flares) alternating with remissions and displaying symptoms that vary widely. In order to evaluate SLE disease activity, a scoring index is commonly used. The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is the most commonly used scoring system to evaluate SLE disease activity (Bombardier C. et al., 1992, Arthritis and Rheumatism, 35(6):630-640). In order to arrive at a SLEDAI score, each patient is examined for the presence of 24 clinical characteristics in the last 10 days. Each clinical characteristic is assigned a value and the sum of these values is the patient's SLEDAI score.
There is no cure for SLE, thus treatment is focused on reducing the severity of symptoms and/or on prevention of symptoms. For many years, standard therapy for SLE included anti-malarials, steroids and immunosuppressive drugs. Though efficient in improving quality of life, survival and well-being, these treatments still induce many undesired side effects.
Publication EP2123280 discloses an agent for prevention and/or treatment of systemic lupus erythematosus, which comprises, in combination, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyrida zine-3-one or a solvate thereof and a corticosteroid.
Publication WO2004/093647 discloses a method for identifying or monitoring SLE in an individual, including quantitating complement component C4d on the surfaces of platelets and comparing the amounts of C4d to reference levels of C4d on platelets of individuals without SLE and/or on platelets of the individual obtained at a different time.
Semaphorins and Semaphorin 3A
Semaphorins are a family of membrane bound and soluble proteins classified into eight sub-classes based on their structural domains. Semaphorins mainly regulate focal adhesion assembly/disassembly and induce cytoskeletal remodeling, thus affecting cell shape, cell attachment to the extracellular matrix, cell motility, and cell migration. Although Semaphorins were originally identified as affecting axon guidance during development of the nervous system, they are now thought to fulfill diverse physiological roles including organogenesis, vascularization, angiogenesis, neuronal apoptosis, and neoplastic transformation. Additionally, recent studies pointed to the involvement of Neuropilin-1 and certain Semaphorins in the regulation of the immune system, and thus these Semaphorins are denoted “immune Semaphorins” (Kikutani H. et al., 2007, Advances in Immunology, 93:121-143).
The seven class-3 Semaphorins (Sema3s), designated by the letters A-G, are the only vertebrate secreted Semaphorins. Neuropilins (Nrps) and the type A/D family Plexins (Plexin-A1, -A2, and -A3, and Plexin-D1) act as receptors for Sema3s. Each Sema3 family member shows distinct binding preference for Nrps. Each Sema3-Nrp complex associates with specific plexins to mediate downstream signaling. Most membrane-bound vertebrate Semaphorins directly bind plexins, while class-3 Semaphorins require Neuropilins as obligate co-receptors.
Semaphorin 3A (Sema3A), a class-3 secreted member of the Semaphorin family, has been established as an axonal guidance factor during development. Interestingly, several lines of evidence suggest that Sema3A also affects immune cell functions. Sema3A has been shown to be expressed by activated T cells and inhibit T cell proliferation and cytokine secretion (Catalano, A et al, 2006, Blood 107: 3321-3329; Lepelletier, Y. et al., 2006, Eur. J. Immunol. 36: 1782-1793). Moreover, the expression of Sema3A, Neuropilin 1 (NP-1), Neuropilin 2 (NP-2), and Plexins was found to be increased on differentiating macrophages and on activated T cells (Ji J D et al., 2009, Human Immunol., 70(4): 211-7). Additionally, Neuropilin-1 expression on regulatory T cells has been shown to enhance interactions with immature dendritic cells (DCs) during antigen recognition, resulting in higher sensitivity to limiting amounts of antigen (Sarris, M. et al., 2008, Immunity, 28: 402-13).
A recent study has shown that overexpression of Sema3A in a mouse model of collagen-induced arthritis resulted in reduced incidence, disease severity, and articular inflammation. Moreover, in line with results in arthritic mice, the study showed a defective Sema3A expression in CD4+ T cells derived from patients with rheumatoid arthritis (Catalano A. et al., 2010, J. Immunol., 185: 6373-83).
In another study, kidney biopsies from lupus glomerulonephritis (LGN) patients showed stronger staining with anti-NP-1, anti-Semaphorin 3A and anti-Semaphorin 4A antibodies as compared with either normal biopsies or biopsies from patients with primary nephropathy and proteinuria (Vadasz Z. et al., 2011, Lupus, 20:1466-1473). A subsequent study has shown that Sema 3A serum levels in SLE patients are significantly lower than in healthy individuals (Vadasz Z. et al, 2012, Arthritis Research & Therapy, 14:R146).
U.S. Application Publication No. 2012/0251539 discloses a method of treating an immune-related disorder in a subject, comprising administering to the subject an effective amount of a Sema3A inhibitor, resulting in reduced Sema3A activity in the subject.
There is still an unmet need, however, for a safe and effective treatment for Systemic Lupus Erythematosus.